Left Ventricular Diastolic Dysfunction in Patients With COPD in the Presence and Absence of Elevated Pulmonary Arterial Pressure*

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1 Orig ina I Research COPD Left Ventricular Diastolic Dysfunction in Patients With COPD in the Presence and Absence of Elevated Pulmonary Arterial Pressure* Georg-Christian Funk, MD; lrene Lang, MD; Peter Schenk, MD; Arschang Valipour, MD; Sylvia Hartl, MD; and Otto Chris Burghuber, MD Background: Increased right ventricular afterload leads to lett ventricular diastolic dysfunction due to ventricular interdependence. Increased right ventricular afterload is frequently present in patients with COPD. The purpose of this study was to determine whether left Ventricular diastolic dysfunction could be detected in with normal or elevated pulmonary artery pressure (PAP). Methode: Twenty-two patients with COPD and 22 matched control subjects underwent pulsed Doppler echocardiography. Left ventricular systolic dysfunction and other causes of left ventricular diastolic dysfunction (eg, coronary artery disease) were excluded in all patients and control subjects. PAP was measured invasively in 13 patients with COPD. Results: The maximal atrial filling velocity was increased and the early filling velocity was decreased in patients with COPD compared to control subjects. The early flow velocity pawlate flow velocity peak (WA) ratio was markedly decreased in patients with COPD compared to control subjects ( vs 1.38 * 0.069, respectively; p < O.OOOl), indicating the presence of left ventricular diastolic dysfunction. The atrial contribution to total left diastolic filling was increased in patients with COPD. This was also observed in with normal PAP, as ascertained using a right heart catheter. The atrial contribution to total left diastolic filling was further increased in with PAP. PAP correlated with the E/A ratio (r = -0.85; p < 0.OOOl). Conclusions: Left ventricular diastolic dysfunction is present in with normal PAP and increases with right ventricular afterload. (CHEST 2008; 133: ) Key words: comorbidity; echocardiography; pulmonary hypertension Abbreviations: %A = percentage contribution of atrial to total right ventricular diastolic filling Amax = late atrial filling; AT = acceleration time; EYA = early flow velocity pealdate flow velocity peak; Emax = early diastolic filline; mpap = mean pulmonruy artery ressure; PAP = pulmonary artery pressure; PEP = preejection period; RVET = right ventricular ejection time; TLC = totaf'lung capacity bnormal patterns of left ventricular diastolic Aflling have been reported in patients with increased right ventricular pressure'-4 and/or volume5.6 load, suggesting that left ventricular filling dynamics may be influenced by right ventricular loading conditions. Several studies7-10 have demonstrated increased right ventricular volumes, reflecting right ventricular afterload, in patients with COPD and mild pulmonary artery hypertension. We have previously observed altered left ventricular filling dynamics despite preserved systolic left ven- tricular function in patients with COPD in the absence of left-sided heart di~ease.~ There are conflicting data with regard to left ventricular diastolic function in with normal elevated pulmonary artery pressure (PAP) as weii as with elevated PAP So far, PAP has not been measured invasively in with suspected left ventricular diastolic dysfunction. Moreover, other sources of left ventricular diastolic dysfunction (eg, systemic arterial hypertension or coronary artery disease) have not been systemically excluded Original Research

2 The purpose of this study was to determine whether left ventricular diastolic dysfunction could be detected in with normal or elevated PAP. Left ventricular diastolic filling was assessed by Doppler echocardiographic methods. Study Subjects MATERIALS AND METHODS Twenty-two patients with COPD and 22 age-matched and sex-matched control subjects were studied. All subjects underwent a physical examination, arterial blood gas analysis (AVL Compact 3 Blood Gas Analyzer; Roche Diagnostics; Graz, Austria), ECG, chest radiograph, and pulmonary function tests (SensorMedics Vmax 22, PFT Unit; Viasys Healthcare; Conshohocken, PA) according to American Thoracic Society standards. Subjects were not eligible if they had any of the following conditions: previous diagnosis; treatment for or evidence of arterial hypertension on clinical examination; diabetes mellitus; alcohol abuse; valvular heart disease; history of sigruficant coronary artery disease, angina pectoris; or mywardial infarction. Sigdicant systemic hypertension or coronary artery disease was ruled out by treadmill exercise tests or additional thallium scintigraphy. Furthermore, we excluded patients with atrial tachprhythmias and/or signs of left venbicular hypertrophy on a standard ECG. Patients in whom adequate visualization of the heart could not be achieved were also excluded from the study. Treatment consisted of inhaled bronchodilators and/or inhaled corticosteroids and theophylline. Therapy with inhaled &-agonists was withdrawn 24 h prior to the study. The study protocol was approved by the ethics committee of the University of Vienna, and informed consent was obtained prior to study entry. Echocardiographic Studies For echocardiography (model SONOS 7500 ultrasound system; Philips; Amsterdam, the Netherlands), standard two-dimensional echocardiographic views were used to obtain standard parasternal, apical, and subcostal views in order to measure systolic and diastolic left ventricular dimensions and for calculations of left ventricular fractional shortening. Measurements of interventricular septum thickness and right ventricular end-diastolic dimensions were obtained from short axis views. Measurements were made according to the conventions of the American Society of Echocardiographers.'4 "From the De artment of Respiratory and Critical Care Medicine (Drs. Fun!, Valipour, Hartl, and Burghuber), Otto Wagner Hospital, Vienna, Austria; and the De artment of Internal Medicine 2 (Dr. Lang), Division of Cardio P ogy, and the Department of Internal Medicine 3 (Dr. Schenk), Intensive Care Unit 13H1, University of Vienna, Vienna, Austria. The authors have reported to the ACCP that no significant conflicts of interest exist with any com aniedorganizations whose products or services may be discusselin this article. Manuscript received November 3, 2007; revision accepted February 11, Reproduction of this article is rohibited without written permission from the American College ofchest Physicians (w.chestjoumal. org/misc/re rintsshtml). Corresponkke to: Otto Chris Bur huber, MD, Department of fispiratoq a d Critical care MefLne, sanntoriumsstra~ 2, A-1 140, Vienna, Austria; otto.burghuber@wienkau.at DOI: /chest The technique of pulsed Doppler echocardiography for the evaluation of pulmonq hernodynamics in patients with chronic hypaxic lung disease has been described elsewhere.15 In this study, a 2.4MHz phased array transducer was used. Doppler flow velocity patterns and simultaneous lead I1 ECG tracings were recorded. The cycles chosen for analysis were those with the highest early flow peaks and the steepest descent of flow velocity early in diastole. The following measurements were obtained from the mitral and tricuspid flow: (1) peak flow velocity of early diastolic filling (Emax); (2) peak flow velocity of late atrial filling (Amax); (3) the early flow velocity pealdate flow velocity peak (E/A) ratio; and (4) the fraction of filling during atrial systole, as defined by the integrated velocity during late filling divided by the total diastolic integrated velocity. The following parameters were obtained in the right ventricular outflow tract: (1) right ventricular ejection time (RVET), defined as the time (in milliseconds) from the onset of ejection to zero flow; (2) acceleration time (AT), defined as the time (in milliseconds) between the onset of ejection to peak flow velocity; and (3) preejection period (PEP), defined as the time (in milliseconds) from Q wave to the onset of ejection. AT and PEP were also expressed as a ratio to the total duration of the RVET (re, AT/RW and PEP/RVET). All measurements were performed by two observers. The data are presented as the average of five or more cardiac cycles. The intraobserver and interobserver variability in patients and control subjects were 6.2% and 7.18, respectively, for transmitral E peak velocity, and 3.5% and 3.98, respectively, for transmitral A peak velocity. Normal values for M-mode and Doppler echocardiographic variables were obtained from the literat~re.~6." Right Heart Catheterization Thirteen patients with COPD consented to undergo right heart catheterization in addition to echocardiography. Their baseline characteristics did not differ from those of the remaining nine patients who did not undergo catheterization. Swan-Ganz balloon catheters (Base TD 831HF7.5; Edwards Lifesciences; Irvine, CA) were used to record systolic PAP and diastolic PAP using transducers (Hewlett Packard; Palo Alto, CA) and a monitor (Merlin; Hewlett Packard). The mean PAP (mpap) was calculated by electronic integration. Normal PAP was defined as an mpap of < 20 mm Hg.18 stattstrcal Analysis All values are expressed as the mean 2 SEM. Comparisons among groups were performed by Student t test or analysis of variance. The Scheffk test was used for post hoc analysis. The relationships among the selected variables were assessed by Pearson correlation coefficient. A p value of < 0.05 was considered to be significant. A statistical software package (SPSS, version 12.0; SPSS; Chicago, IL) was used for analysis. RESULTS Patient Characteristics Table 1 shows the clinical characteristics and lung function data of the study population. The FEV, was sigx-&cantly lower and total lung capacity (TLC) was significantly higher in patients with COPD compared with control subjects. On the basis of FEV,, CHEST I JUNE,

3 Table l-clinical Churacteristice and Selected Lung Function Parametem in the Study Groups* Healthy Patients Volunteers With COPD Variables (n = 22) (n = 22) p Value Age, F Weight, kg Height, cm Heart rate, beatdrnin BP, mm Hg Systolic Diastolic vc, L FEV,, L TLC, L Paon, min Hg 54.8 * t t ? NS 78 t 3.0 NS NS 76.4 t 2.6 NS NS NS NS 1.8 t 1.9 < o.oo < < o.oo01 *Values are given as the mean 2 SEM, unless othewise indicated. NS = not significant; VC = vital capacity. five patients had stage I1 disease (C 80 to >50% predicted), nine patients had stage I11 disease (< 50 to >30% predicted), and eight patients had stage IV disease (< 30% predicted) according to the Global Initiative for Chronic Obstructive Lung Disease guidelines.19 In addition, Pao, was significantly lower in patients with COPD. With respect to echocardiographic measurements, left ventricular systolic and diastolic diameters were normal and not different between the groups. The mean left ventricular fractional shortening values in control subjects and patients with COPD were % and 40.5 k 2.1%, respectively. There was no difference in interventricular septum thickness ( vs mm, respectively) between the groups. However, the right ventricular end-diastolic diameter was significantly higher in patients with COPD compared with control subjects ( vs mm, respectively; p < 0.005) but was still within normal limits. Doppler Measurements Bight Ventricle: Right ventricular systolic time intervals (ie, AT, RVET, and PEP) were shorter in patients with COPD compared with control subjects (Table 2); however, PEP/RVET and AT/FWET ratios did not differ significantly, reflecting similar systolic right ventricular performance. In patients with COPD, the peak velocity of Amax was higher, the E/A ratio was lower, and the percentage contribution of atrial to total right ventricular diastolic filling (%A) were higher compared with recordings from control subjects. No correlation was found between right ventricular systolic time intervals and right ventricular diastolic flow velocities. Table %Right Ventricular Systolic Time Intervals* Healthy Patients With RV Systolic Time Volunteers COPD Intervals (n = 22) (1) = 22) AT, ms RVET, ms PEP, ms AT/RVET ratio PEPIRVET ratio RV diastolic filling variables Emax, cm/s Amax, cm/s E/A ratio %A, % t t t t f * 7.7t lt 0.36 t t lt 58.4 t 3.lt ~~ ~ *Values are given as the mean t SEM. RV = right ventricular. fp < Left Ventricle: Doppler variables of diastolic function for the control group were within the established normal limits. However, compared with control subjects, the Emax was lower ( vs cm/s, respectively; p < 0.001) and the Amax was higher (71.1 k 3.5 vs 49.9? 2.3 cmh, respectively; p < ) in patients with COPD (Table 3). Thus, the E/A ratio was lower in patients with COPD (p < ). In addition, patients with COPD had a significantly higher %A ( cds) than subjects in the control group ( cds). We observed a good correlation between the E/A ratio and %A with FEV, (E/A ratio and FEV,: r = 0.63; p < ; %A and FEV1: r = -0.68; p<o.oool) and Pao, (E/A and Pao,: r= 0.60; p < 0001; %A and Pao2: r = -0.56; p < 0,001). Furthermore, the AT correlated with the E/A ratio (T = 0.56; p < ) and %A (r = -0.54; p < ). Table %Mean Values for kfi Ventricular Diastolic Filling Variables in 22 COPD Patients Compared With 22 Control Subjects Variables Mean SD SEM p Value Emax, cm/s Amax, cm/s EIA ratio %A, % OOO O.OOO O.OOO Original Research

4 Right Heart catheterization Measurements In 13 of our 22 patients with COPD, invasive measurements of PAP were obtained. Anthropometric data, BP, and heart rate were not different between with normal or elevated PAP (data not shown). were divided into two groups according to resting mpap. Six patients had normal mpap (18.57 * 0.43 mm Hg), and seven patients had elevated mpap ( mm Hg; p < 0.001). FEV, ( % vs % predict4 p < 0.OOOl) and Pao, ( vs mm Hg; p<o.oool) were significantly lower in patients with elevated mpap. There was no difference in TLC and vital capacity between the groups. Although there was a tendency toward a lower EIA ratio in patients with elevated PAP ( ) compared to those without ( ), this was not statistically significant (Fig 1). However, the fraction of diastolic filling during atrial systole was significantly higher in with elevated PAP ( %) compared to those with normal PAP (55.6? 3.7%; p < 0.01) [Fig 21. In addition, there was a good correlation between mpap and both E/A ratio (r = -0.85; p < ) and %A (r = 0.62; p < 0.01). with normal mpap had decreased E/A ratio and increased %A compared to control subjects (Fig 1, 2). DISCUSSION The main finding of the present study was the evidence obtained for left ventricular diastolic dysfunction in patients with COPD compared to age- E/A ratio controls COPD - PH COPD +PH FIGURE 1. The EIA ratio in 22 control subjects and in COPD patients with elevated PAP (n = 7) and normal PAP (n = 6) PAP. x = p < 0.01 (control subjects vs ). Values are given as the mean? SEM n - %A 7 controls COPD - PH COPD + PH FIGURE 2. The %A in 22 control sub'ects and in with normal PAP (n = 6) and elevated PAP (n = 7). X = p < 0.01 (control subjects vs ); t = p < 0.01 (COPD patients with elevated PAP vs without elevated PAP). Values are mean? SEM. matched and sex-matched control subjects despite otherwise normal left ventricular systolic function. Furthermore, we observed an increased atrial contribution to left ventricular filling. Notably, left ventricular diastolic dysfunction was also present in with normal PAP. Prevalence rates of left ventricular systolic dysfunction in patients with COPD range from 4 to 32% and are usually associated with concomitant coronary heart disease However, very few studies'l-13 have reported on the echocardiographic features of diastolic function in patients with COPD. Various mechanisms might explain the presence of left diastolic dysfunction in. Patients with COPD experience chronic hypoxemia, which might result in abnormalities of myocardial relaxation as a consequence of myocyte hypoxia due to intracellular calcium transport disturbances For multiple reasons, pulmonary hypertension with chronic right ventricular pressure overload and consecutive right ventricular hypertrophy may develop in COPD ~atients.2~327 The ventricle becomes less compliant, diastolic function decreases, and finally the right ventricle dilates.% Under these circumstances, during early diastole, the ventricular septum displaces toward the left ventricular cavity and the left ventricle becomes distorted from its circular configuration. The severity of left ventricular and septal deformity depends on the transseptal pressure gradient.*pm This ventricular interaction may cause impaired left ventricular filling,3-4,6.29jo which is consistent with our findings. In the present report, we observed an increased atrial contribution to total CHEST / 133 / 6 /JUNE,

5 diastolic filling in patients with COPD indicating reduced Emax and a compensatory increase in late diastole at a time when septal geometry is less deranged.4929j1 These concepts of left diastolic dysfunction are based on the presence of pulmonary hypertension and/or hypoxemia, neither of which was present in our study. As a limitation, pulmonary hemodynamics and oxygenation during exercise were not determined in this study. Boussuges et all1 reported similar results in 34 patients with moderate-to-severe COPD using combined analysis of pulmonary venous and mitral blood flow velocities. In concordance with our data, the authors observed impaired left ventricular filling and an increased contribution of atrial contraction to left ventricular f i g despite normal systolic left ventricular function in their patients compared with control subjects. However, they acknowledged that their patients had a sigmficantly higher heart rate than control subjects, which might have influenced their results since tachycardia shortens the diastolic filling period and atrial contraction may have occurred before the early filling was completed. Furthermore, it remained unclear from their results whether the presence or degree of pulmonary hypertension is related to left ventricular diastolic function in patients with COPD. In order to investigate this relationship between PAP and left ventricular diastolic dysfunction, we studied with invasively ascertained normal PAP values. Notably, we observed that with normal PAP also had impaired right ventricular and left ventricular diastolic filling patterns compared with control subjects. This may be caused by the increased right ventricular diameters observed in these patients, although end-diastolic right ventricular parameters were still within normal limits. Nevertheless, this modest right ventricular enlargement may be clinidy sign&- cant, resulting in right ventricular diastolic dysfunction, which in turn leads to left ventricular filling impairment recognized by Doppler measurements. In the COPD patient group with elevated PAP, we found a more pronounced impaired left ventricular diastolic filling pattern, indicating that overt pulmonary artery hypertension causes more severe left ventricular filling impairment. Thus, it has been suggested13 that altered left ventricular filling is mainly caused by right ventricular afterload conditions via the mechanism of ventricular interdependence. The concept of left-sided diastolic dysfunction owing to increased right ventricular load via ventricular interdependence is supported by observations from patients with severe emphysema.10 These patients had increased pulmonary capillary wedge pressure, which correlated positively with both mpap and right atrial pressure. COPD with lung hyperinflation and distension leads to increased stiffness of the parietal pleura and thus of the walls of the cardiac fossa.32 This could lead to an added load on the ventricles imposed by the need to deform the surrounding tissues owing to the conformational changes of the heart during the cardiac cycle. The stiffness of the walls of the cardiac fossa might contribute to left and right diastolic dysfunction in patients with COPD, independent of pulmonary hypertension.= Various other pathophysiologic mechanisms play a role in the development of altered diastolic left ventricular filling. Left ventricular wall thickness seems to be of physiologic importance, as ventricular thickness may prolong the isovolumetric relaxation period and thereby lead to reduced early peak velocities and a change in the E/A ratio. However, in the present study the interventricular thickness was similar between the groups. Other factors should also be considered when interpreting the results of our study. With increasing age, early filling decreases and the contribution of the atrial contraction increases. However, in the present study, patients with COPD and control subjects were matched for age, height, weight, and BP. In addition, we made an attempt to rule out other possible variables that have been shown to influence left ventricular filling, such as systemic arterial hypertension, alcohol abuse, and diabetes mellitus. In particular, significant coronary artery disease was ruled out in all patients. It is important to understand these pathophysiologic processes in managing with left-sided diastolic dysfunction, since this hemodynamic disturbance may have a clinical implication in patients with arrhythmias (particularly, atrial fibrillation), resulting in a loss of atrial systole and/or a shortening of the diastolic filling period. Left ventricular diastolic filling characteristics can be easily obtained by a noninvasive echocardiographic approach. Moreover, it has been demonstrated that increased velocity during late diastolic filling of the right ventricle is associated with increased mortality in patients with chronic pulmonary disease.34 In conclusion, we demonstrated altered left ventricular filling with redistribution from early to late diastole in patients with stable COPD. Left ventricular diastolic dysfunction is also present in COPD patients with normal PAP. The mechanisms described above seem to be complex. However, the cardinal determinant seems to be diastolic ventricular interplay by means of a geometric interaction through the common ventricular septum. ACKNOWLEDGMENT: We thank Mrs. I. lmkova for her help in data abstraction. We appreciate the skilled technical assistance of Mrs. D. Sponner, J. Sighart, and Kora Geyer Original Research

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